An area of current research focus in the pharmaceutical industry is the development of methods for the controlled or sustained release of drugs. Such methods obviate certain problems associated with traditional methods for administering drugs, such as noncompliance of patients with a prescribed medication schedule, the need for multiple injections, and fluctuating concentrations of the drug in the body. These problems are particularly acute when the drug is a protein or peptide. Such drugs frequently have short in vivo half-lives. In addition, protein-based drugs cannot be administered orally in an unprotected state due to the rapid degradation that occurs in the digestive tract.
Methods for sustained or controlled drug release can utilize an implanted device, such as an osmotic pump, or a drug dispersed in a biocompatible polymer matrix, which can be implanted, administered orally or injected. Polymers often used in such applications include poly(lactic acid) and poly(lactic acid-co-glycolic acid). Both polymers undergo slow hydrolysis in vivo, releasing the entrapped drug. The polymer degradation products are the parent acids, which are absorbed by the body.
Polymer/drug matrix particles to be administered via injection must have a size range typically on the order of 200 microns or less. The size and morphology of polymer/drug matrix particles depends upon the fabrication method employed, and the formation of small polymer/drug matrix particles in which the drug is a protein is currently limited to a few techniques. For example, polymer/protein matrix particles comprising poly(lactic acid) and either trypsin or insulin, were prepared by both an oil/water emulsion method and a neat mixing method at elevated temperature (Tabata et al., J. Cont. Release 23: 55-64 (1993)). The polymer/protein matrices thus formed were subsequently ground into granules. The granules prepared by the neat mixing method lost a significant fraction (10%) of protein activity, possibly due to the heating step. These granules also suffered from a large initial burst of protein release. The granules prepared by the oil/water emulsion method lost an even greater amount (about 40-60%) of protein activity, possibly caused by protein lability with respect to the oil.
A method for forming injectable polymer/drug matrix microparticles was disclosed by Wise (Wise in Biopolymeric Controlled Release Systems, Vol.1, Wise, ed., CRC Press:Boca Raton, Chapter 8 (1984)). Microparticles comprising poly(lactic acid-co-glycolic acid) and the narcotic antagonist naltrexone were formed by cryogenic grinding of beads or rods of a solid polymer/naltrexone matrix. The beads and rods were formed by molding a polymer/naltrexone matrix film into the desired shape at a temperature above the softening point of the polymer. Thus, this method is not suitable for the preparation of polymer/drug matrix microparticles incorporating a thermally labile drug, such as many proteins, peptides and polynucleotides and analogs.
Another example, disclosed in U.S. Pat. No. 5,019,400, issued to Gombotz et al., the contents of which are incorporated herein by reference, is a method for producing polymer/protein microspheres. This method involves atomizing a mixture comprising a biocompatible polymer and a drug substance, and freezing the resulting aerosol droplets. In this method, particle size and shape depend upon the method of atomization and the flow rate of the polymer solution through the atomizer. A number of variables are tightly controlled in order to optimize reproducibility in particle sizes and morphologies.
Current methods for the formation of polymer/drug matrix implants suffer from drawbacks when utilized with thermally labile or organic solvent labile drugs. These methods employ harsh conditions, such as elevated temperatures (greater than about 45.degree. C. and/or aqueous/organic emulsions, which can result in a significant loss of drug activity. Other methods utilize a simple mixture of bulk polymer with solid drug, which does not yield a fine microscopic dispersion of the drug within the polymer matrix, resulting in a more erratic drug release in vivo.
The need exists for a method for forming polymer/drug matrix devices suitable for injection or implantation in which the solid polymer/drug matrix is formed by methods suitable for thermally sensitive drugs, as well as drugs sensitive, under certain conditions, to organic solvents, while still achieving a substantially uniform distribution of the drug throughout the matrix. In addition, the method must be amenable to scale-up, and to performance in a closed, sanitized environment to enable the efficient, economical manufacture of polymer/drug matrix controlled release devices meeting FDA sterility requirements.